| Autor: |
Marks, Christian R., Shonesy, Brian C., Wang, Xiaohan, Stephenson, Jason R., Niswender, Colleen M., Colbran, Roger J. |
| Zdroj: |
Molecular Pharmacology; 2018, Vol. 94 Issue: 6 p1352-1362, 11p |
| Abstrakt: |
Ca2+/calmodulin-dependent protein kinase II (CaMKII) and metabotropic glutamate receptor 5 (mGlu5) are critical signaling molecules in synaptic plasticity and learning/memory. Here, we demonstrate that mGlu5is present in CaMKIIαcomplexes isolated from mouse forebrain. Further in vitro characterization showed that the membrane-proximal region of the C-terminal domain (CTD) of mGlu5adirectly interacts with purified Thr286-autophosphorylated (activated) CaMKIIα. However, the binding of CaMKIIαto this CTD fragment is reduced by the addition of excess Ca2+/calmodulin or by additional CaMKIIαautophosphorylation at non-Thr286 sites. Furthermore, in vitro binding of CaMKIIαis dependent on a tribasic residue motif Lys-Arg-Arg (KRR) at residues 866–868 of the mGlu5a-CTD, and mutation of this motif decreases the coimmunoprecipitation of CaMKIIαwith full-length mGlu5aexpressed in heterologous cells by about 50%. The KRR motif is required for two novel functional effects of coexpressing constitutively active CaMKIIαwith mGlu5ain heterologous cells. First, cell-surface biotinylation studies showed that CaMKIIαincreases the surface expression of mGlu5a. Second, using Ca2+fluorimetry and single-cell Ca2+imaging, we found that CaMKIIαreduces the initial peak of mGlu5a-mediated Ca2+mobilization by about 25% while doubling the relative duration of the Ca2+signal. These findings provide new insights into the physical and functional coupling of these key regulators of postsynaptic signaling. |
| Databáze: |
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